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Investigators at the Keck School of Medicine of the University of Southern California (USC) have discovered that iron plays a key role in causing inflammation in the lungs during an allergic asthma attack. They showed that regulating iron uptake by a group of immune cells in the lungs shows promise as a treatment for asthma and other allergic diseases.

The research, published in Science Translational Medicine, identified a group of immune cells known as group 2 innate lymphoid cells (ILC2s) that become overactive during an asthma attack causing excessive inflammation and tightening of the airways. To date, the underlying causes that drive the overactivity of ILC2s has been poorly understood, but the new findings by the Keck researchers, reveals new details on the mechanism behind this link, which shows these immune cells depend on iron to generate energy.

“This is the first time it’s been shown that iron is an important metabolic regulator of pulmonary immune cells such as ILC2s, allowing them to generate energy,” said lead author Benjamin Hurrell, PhD, a research assistant professor of molecular microbiology and immunology at the Keck School of Medicine. “That’s helpful for treating disease, because targeting a cell’s energy can allow us to selectively increase or decrease its function.”

For their research, the investigators conducted experiments using both mouse models and human cells and discovered that ILC2s use iron to support a number of different cellular processes, making it a central player in the activation of immune cells. The team demonstrated that in human cells, increased ILC2 activity and iron uptake correlated to the severity of asthma, while mouse studies showed that preventing iron uptake in ILC2s reduced the severity of symptoms.

The new findings build on broader research from the lab of Omid Akbari, PhD, a professor of molecular microbiology and immunology at Keck, on the role of ILC2s. During the current study, the researchers worked closely with peers in Keck’s department of medicine to aid in quickly advancing these findings to the clinic.

“We have limited drugs besides steroids for patients with asthma,” noted Akbari, the study’s senior author. “Steroids inhalers and pills can control symptoms to keep patients alive, but they are not attacking the underlying pathophysiology of the disease. We hope our research can ultimately offer a better solution.”

Iron’s role in asthma

To better understand the role that iron plays in allergic asthma symptoms and severity, the Keck researchers began with a series of mechanistic studies. Iron in the body enters cells by binding to the protein transferrin. Using a traceable form of transferrin, the team introduced an allergen to activate ILC2s and showed that the traceable transferrin entered the cells, which proved iron uptake by the cells. They confirmed these initial findings using deferiprone, an iron chelator used to treat patients with an iron overload condition known as hemochromatosis, which showed the same results.

The team next turned to single-cell RNA sequencing to analyze the transcriptomes of ILC2s, to show iron is an integral part of the pathway for energy production in these cells.

The investigators are optimistic that their research has identified a viable therapeutic target that addresses the root causes of allergic asthma, as opposed to the current steroidal treatments that focus solely on reducing the severity of symptoms.

“We can’t deplete a biological system of iron, which is an essential element for transporting oxygen in the body,” Akbari noted. “But restricting iron availability to immune cells in the lungs could reduce the exacerbation of asthma during an acute attack. This approach also paves the way for treating other lung immune-mediated and inflammatory diseases, such as COVID-19.”

Beyond allergic asthma, the findings have the potential to inform therapy development for other allergic conditions where it is known that ILC2s become overactive such as eczema, dermatitis, hay fever, and even food allergies.

Next steps for the Keck team is to find methods that can find a restricted method of targeting ILC2s in the lungs to reduce iron uptake locally without affecting the important role iron plays in other systems in the body.

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